Jane Agergaard

Agergaard 2009 Agergaard, Jane. 2009. Randomised study of not providing diphtheria-tetanus-pertussis vaccine together with or after measles vaccination: Impact on morbidity and growth. Bandim Health Project, Statens Serum Institut. Faculty of Health Sciences, Aarhus University.
Many observational and a few randomised studies have shown there may be non-specific effects of vaccinations on all cause mortality in low-income countries. Vaccination with live vaccines, like measles vaccine (MV), seems to lower morbidity and mortality more than can be explained by prevention of measles. In contrast, killed vaccines, like diphtheria-tetanus-pertussis (DTP), have been associated with increased morbidity and mortality in areas with herd immunity to pertussis. The nonspecific effects are most pronounced for girls, and the effect of DTP may only be present for girls. The non-specific effects are observed as long as a given vaccine is the most recent vaccine. Simultaneous vaccination with DTP and MV has also been associated with increased mortality. We conducted a randomised trial to examine the effect of DTP given together with or after MV on mortality, morbidity and growth.

Not providing DTP together with or after MV is associated with lower mortality and morbidity and better growth.

The study was carried out at the Bandim Health Project, a health and demographic surveillance system (HDSS) site in Bissau, Guinea-Bissau. More than 6000 children between 9 months and 4 years were randomised to DTP or no DTP in two groups depending on MV status. Those missing MV were randomised to MV+DTP+OPV MV+OPV; those who had received MV were randomised to DTP booster+OPV or OPV.

The cohort was followed by regular 3-monthly visits within the HDSS. In subgroup studies we registered symptoms and signs of morbidity more intensively, we collected growth measures, and we collected blood samples before vaccination, at 6 weeks and at 6 months after vaccination for C. pneumoniae and suPAR-analyses. Consultations and hospitalisations were registered daily at the three health centres in the study area and at the only paediatric ward in Bissau. Due to sex differences in the effect of vaccines in previous studies we analysed all data stratified by sex.

As expected DTP was associated with increased risk of side-effects in the first 3 days following vaccination. Overall, there was no effect of DTP on morbidity or growth after the first 3 days of adverse events had passed. However, we found sex-differential effects of DTP in several outcomes. All these sex-differences went in the same direction, with more morbidity in girls and less in boys. Children randomised to MV+DTP+OPV compared with DTP+OPV had sex-difference in growth with p-values for interaction between sex and DTP for weight-for-age z-score of p=0.02 at 6 months and p=0.01 at 9 months after vaccination. Girls who had DTP had significantly lower weight-for-age at 6 months and height-for-age at 9 months. Febrile diseases with vesicular rash were more common in children randomised to MV+DTP+OPV compared with DTP+OPV. In children randomised to DTP-booster+OPV or OPV we found sex-differences in symptoms of morbidity during the first month. (7 to 31 days) after randomisation (p=0.03 for interaction between sex and DTP) and boys were less often hospitalised (p=0.05 for interaction between sex and DTP). C. pneumoniae seroprevalence was high (12%) and lgG-positivity rapidly waning, especially in children with low weight-for-age. There was no overall effect of DTP, but children with normal weight had sex-differential effect of DTP on serological signs of C. pneumonia infection. SuPAR-levels were high with a median of 3.8 ng/ml and did not differ between randomisation groups. Surveillance of pertussis showed that 3% of children presenting cough at consultations had a B. pertussis PCR-positive naso-pharyngeal swab.

In accordance with earlier observations this randomised study showed sex-differential effects of DTP with trends for increased morbidity in girls. More randomised studies are needed and it will be to explore the immunological background. A simple change in the sequence of vaccinations may prevent deaths and improve health.